A Convenient Synthesis of Novel N′-tert-Butyl-N′-Substituted Benzoyl-N-(Substituted Phenyl)aminocarbonylhydrazines and Their Derivatives

Article abstract of DOI:10.1081/SCC-120027261

N-tert-butyl-N-substituted benzoylhydrazines were prepared in two convenient procedures with good yields, subsequent reaction with substituted phenylisocyanates in 1,2-dichloroethane provided a series of novel N′-tert-butyl-N‰-substituted benzoyl-N-(substituted phenyl)aminocarbonylhydrazines. Further treatment with oxalyl chloride gave their derivatives in good yields. The title compounds exhibit moderate larvicidal activities and anticancer activities.

Full text of DOI:10.1081/SCC-120027261

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A Convenient Synthesis of Novel N′-tert-
Butyl-N′-Substituted Benzoyl-N-(Substituted
Phenyl)aminocarbonylhydrazines and Their
Derivatives
Qingmin Wang a & Runqiu Huang a
a State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-
Organic Chemistry , Nankai University , Tianjin, 300071, P.R. China
Published online: 18 Oct 2011.
To cite this article: Qingmin Wang & Runqiu Huang (2004) A Convenient Synthesis of Novel N′-tert-Butyl-N′-
Substituted Benzoyl-N-(Substituted Phenyl)aminocarbonylhydrazines and Their Derivatives, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 34:2, 255-264, DOI: 10.1081/
SCC-120027261
To link to this article: http://dx.doi.org/10.1081/SCC-120027261
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 2, pp. 255–264, 2004
A Convenient Synthesis of Novel N0-tert-
Butyl-N0-Substituted Benzoyl-N-(Substituted
Phenyl)aminocarbonylhydrazines and
Their Derivatives
*
Qingmin Wang and Runqiu Huang
State Key Laboratory of Elemento-Organic Chemistry, Research Institute
of Elemento-Organic Chemistry, Nankai University, Tianjin, P.R. China
ABSTRACT
N-tert-butyl-N-substituted benzoylhydrazines were prepared in two
convenient procedures with good yields, subsequent reaction with
substituted phenylisocyanates in 1,2-dichloroethane provided a series of
novel N0-tert-butyl-N0-substituted benzoyl-N-(substituted phenyl)amino-
carbonylhydrazines. Further treatment with oxalyl chloride gave their
derivatives in good yields. The title compounds exhibit moderate larvi-
cidal activities and anticancer activities.
Key Words: N0-tert-Butyl-N0-substituted benzoylhydrazine; Phenyliso-
cyanate; Benzoylphenylurea; Insect growth regulators.
*
Correspondence: Runqiu Huang, State Key Laboratory of Elemento-Organic
Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, P.R. China; Fax: 0086-022-23503438; E-mail: wang98h@263.net.
255
DOI: 10.1081/SCC-120027261
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Wang and Huang
In contrast to traditional pesticides, benzoylphenylurea (BPU) and its
derivatives mainly control the growth and development process of insects by
interfering with chitin biosynthesis and breeding, and the activities of BPUs
are attributed to the structures of the urea linkage.[1,2] Moreover, N-tert-butyl-
N,N0-diacylhydrazines (TBDH) as a new class of insect growth regulators
(IGR) have been found to mimic the action of 20-hydroxyecdysone to activate
the ecdysone receptor, leading to lethal premature molting.[3–7] Relationships
between the structure and biological activity of the N-tert-butyl-N,N0-
dibenzoylhydrazine larvicides have been extensively investigated. The results
indicated that the molecular hydrophobicity is favorable to insecticidal
activity and N-tert-butyl-N-benzoylhydrazine is the biologically active
unit.[8–12]
In the course of our studies on diacylhydrazine as novel IGRs,[13–15] we
combined the bioactive units of TBDH and BPU to design and synthesize
novel N-tert-buty1-N0-substituted benzoyl-N-(substituted phenyl)aminocar-
bonylhydrazines and their derivatives in order to find a new lead compound
with unusual biological properties and a different spectrum of activities.
N-tert-Butyl-N-substituted benzoylhydrazines are important intermedi-
ates in synthesis of N-tert-butyl-N,N0-dibenzoylhydrazine derivatives and
three synthesis methods of such compound have been published as exempli-
fied below. (1) N-tert-Butylhydrazine was reacted with di-tert-butyldi-
carbonate to afford N-tert-butyloxycarbonyl-N0-tert-butylhydrazine, then
condensation with benzoylchloride and deprotection using hydrochloric acid
yielded N-tert-butyl-N-benzoylhydrazine in 38% yield;[16] (2) N-tert-
butylhydrazine was reacted with N-(9-fluorenylmethylcarbonyl)succinimide
to afford N-tert-butyl-N-(9-fluorenylmethylcarbonyl)hydrazine, then acyla-
tion and deprotection using piperidine provided N-tert-butyl-N-substituted
benzoylhydrazine;[8] and (3) N-tert-butyl-N0-acetonehydrazine prepared from
N-tert-butylhydrazine and acetone was condensation with substituted
benzoylchloride, then deprotection using hydrochloric acid afforded N-tert-
butyl-N-substituted benzoylhydrazine.[17] However, all of these methods have
some respective problems. In the methods (1) and (3), the yields are low
(,50%). The method (2) is not economically profitable, because an expensive
N-(9-fluorenylmethycarbonyl)succinimide is used. Herein we report the
syntheses of N-tert-butyl-N-substituted benzoylhydrazines by two novel
procedures as shown in Schs. 1 and 2.
Method 1. Benzyl alcohol was treated with triphosgene [bis(trichloro-
methyl)carbonate] to obtain benzyl chloroformate in good yield. This
convenient synthesis of benzyl chloroformate avoids the use of phosgene gas
and the complicated experimental set-up associated with it. Benzyl chloro-
formate was condensed with tert-butylhydrazine hydrochloride to give N-tert-
butyl-N0-benzyloxycarbonylhydrazine (1), and subsequent acylation with

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Benzoyl-N-(Substituted Phenyl)aminocarbonylhydrazines
257
Scheme 1.
Scheme 2.
substituted benzoyl chlorides yielded the N-tert-butyl-N0-benzyloxycarbonyl-
N-substituted benzoylhydrazines (2). Further deprotection using 5% Pd-C as a
catalyst provided N-tert-butyl-N-substituted benzoylhydrazines (3) in good
yields as shown in Scheme 1 and Table 1. This highly efficient method for the
synthesis of N-tert-butyl-N-substituted benzoylhydrazines enjoys a number of
advantages in that the reaction is carried out under mild conditions in good
Table 1. N-tert-butyl-N-substituted benzoylhydrazine
yield using 5% Pd-C catalyst.
Isolated yield (%)
Entry
Xn
1 ! 2a–e
2a–e ! 3a–e
a
b
c
H
90
83
86
91
87
96
92
96
90
82
3,5-Me2
2-F
2-Cl
d
e
2,4-Cl2

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Wang and Huang
Table 2. N-tert-butyl-N-substituted benzoylhydrazine yield
using sodium hydroxide.
Isolated yield (%)
Entry
Xn
4 ! 5a, 5f–g
5a, 5f–g ! 3a, 3f–g
a
f
H
81
77
81
76
73
78
3-Me
4-OMe
g
yields, the starting materials are cheap a easily prepared, the experimental
procedure is very simple and this method may be applicable to large scale
production.
Method 2. Phenyl chloroformate was treated with tert-butylhydrazine
hydrochloride to obtain N-tert-butyl-N0-phenyloxycarbonylhydrazine (4), and
subsequent acylation with substituted benzoyl chloride yielded the N-tert-
butyl-N0-phenyloxycarbonyl-N-substituted benzoylhydrazines (5). Further
deprotection using sodium hydroxide provided N-tert-butyl-N0-substituted
benzoylhydrazines (3) as shown in Scheme 2 and Table 2. As a consequence
of its practical simplicity and high efficiency, this new method has already
been applied to the preparation of N-tert-butyl-N-substituted benzoylhydra-
zines in our laboratory.
The reactions of the N-tert-butyl-N-substituted benzoylhydrazines (3)
with substituted phenylisocyanates in 1,2-dichloroethane provided N0-tert-
butyl-N0-substituted benzoyl-N-(substituted phenyl)aminocarbonylhydrazines
(6) as shown in Sch. 3 and Tables 3–5. The structures of the title compounds 6
were confirmed by 1H NMR and IR and mass spectra and elemental analysis.
For example, for 6f, 3343 cm21 (s) corresponds to an N–H stretching
absorption band, 1720 cm21 (s) and 1621 cm21 (s) to C55O stretching
absorption bands, 1392 cm21 (s) and 1360 cm21 (s) to the C–H absorption
bands in the But group. The EI-MS of the title compound 6f gives the
molecular ion peaks (373.20, Mþ) and those of the main fragments.
Treatment of the N0-tert-butyl-N0-substituted benzoyl-N-(substituted
phenyl)aminocarbonylhydrazines (6) with oxalyl chloride gave the colorless
Scheme 3.

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Benzoyl-N-(Substituted Phenyl)aminocarbonylhydrazines
259

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Wang and Huang
Table 4. 1H NMR data for 6a–m and 7m.
d (ppm) (DMSO-d6)
Entry
6a
6b
6c
1.46(s, 9H, But), 6.84–7.50(m, 10H, Ph), 8.39(s, 1H, NH), 8.54(s, 1H, NH).
1.45(s, 9H, But), 6.97–7.72(m, 9H, Ph), 8.44(s, 1H, NH), 8.56(s, 1H, NH).
1.45(s, 9H, But), 3.66(s, 3H, OMe), 6.74–7.44(m, 9H, Ph), 8.17(s, 1H, NH),
8.44(s, 1H, NH).
6d
6e
6f
1.45(s, 9H, But), 7.13–7.63(m, 8H, Ph), 8.77(s, 1H, NH), 8.86(s, 1H, NH).
1.46(s, 9H, But), 1.83(s, 6H, Me), 6.96–7.39(m, 8H, Ph), 8.66(br., 1H, NH).
1.44(s, 9H, But), 2.20(s, 6H, Me), 6.94–7.27(m, 7H, Ph), 8.52(s, 1H, NH),
8.56(s, 1H, NH).
6g
6h
6i
1.52(s, 9H, But), 7.00–7.64(m, 8H, Ph), 8.34(s, 1H, NH), 8.56(s, 1H, NH).
1.52(s, 9H, But), 7.04–7.52(m, 8H, Ph), 8.32(s, 1H, NH), 8.42(s, 1H, NH).
1.52(s, 9H, But), 6.80–7.52(m, 9H, Ph), 8.20(s, 1H, NH), 8.40(s, 1H, NH).
1.46(s, 9H, But), 6.86–7.94(m, 8H, Ph), 8.34(s, 1H, NH), 8.61(s, 1H, NH).
1.52(s, 9H, But), 2.26(s, 6H, Me), 6.56–7.44(m, 7H, Ph), 8.22(s, 1H, NH),
8.40(s, 1H, NH).
6j
6k
6l
1.50(s, 9H, But), 6.72–7.60(m, 8H, Ph), 8.20(s, 1H, NH), 8.48(s, 1H, NH).
1.45(s, 9H, But), 7.16–7.42(m, 9H, Ph), 8.36(s, 1H, NH), 8.6 1(s, 1H, NH).
1.59(s, 9H, But), 7.01–7.38(m, 9H, Ph).
6m
7m
Table 5. IR data for 6a–m and 7m.
Entry
IR (cm21) (KBr)
6f
3343, 3114, 2964, 1720, 1621, 1594, 1533, 1490, 1392, 1360, 1223, 1190,
1090, 852, 822, 757, 691, 618.
6m
7m
3371, 3255, 2995, 1691, 1626, 1590, 1532, 1501, 1395, 1366, 1218, 1197,
824, 706, 699, 604.
3092, 2975, 1790, 1753, 1695, 1492, 1392, 1311, 1190, 804, 741, 699.
crystalline products (7) in good yields (.70%) as shown in Sch. 4. The
1
structures of the title compounds 7 were confirmed by H NMR and IR and
mass spectra and elemental analysis. For example, for 7m, 1790 cm21 (s),
1753 cm21 (S) and 1695 cm21 (s) to C55O stretching absorption bands,
Scheme 4.

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Benzoyl-N-(Substituted Phenyl)aminocarbonylhydrazines
261
1392 cm21 (s) and 1311 cm21 (s) to the C–H absorption bands in the But
group. The EI-MS of the title compound 7m gives the molecular ion peaks
(399.15, Mþ) and those of the main fragments.
The larvicidal activities of the title compounds (6) and (7) and N-tert-
butyl-N,N0-dibenzoylhydrazine (RH5849) were evaluated using previously
reported procedure.[7,16,18,19] The larvicidal activities show that the title
compounds (6) and (7) exhibit moderate larvicidal activities. For example, at
1000 ppm, the percent mortality of compounds 6f, 6k and RH5849 is 75.0%,
82.5% and 100%, respectively. Toxicity assays indicated that the title
compounds (6) and (7) can induce a premature, abnormal and lethal larval
molt. The symptoms of toxicity included discoloration, weight loss, cessation
of feeding, and developmentally premature, lethal molting at higher rates.
We have found that the title compounds (6) possess anticancer activities in
vitro. The anticancer activity was assayed by the MTT or SRB methods.[20–23]
For example, at 1000 mM, the inhibition rate of compound 6c to P388 and
A-549 is 29.8% and 29.2%, respectively. The inhibition rate of compound 6b
to HL-60 and BEL-7402 is 33.3% and 21.6%, respectively.
EXPERIMENTAL
All the melting points were determined with Thomas-Hoover melting
point apparatus, the thermometer was not standardized. IR spectra were
1
recorded with a Shimadzu-435. H NMR spectra were recorded with Bruker
AC-P200 using tetramethylsilane as an internal standard. Mass spectra were
recorded with HP5988A spectrometer using the EI method. Elemental
analysis was carried out with a Yanaco CHN Corder MT-3 elemental analyzer.
N-tert-Butyl-N-substituted benzoylhydrazines 3a–e. To a solution of
N-tert-butyl-N-benzyloxycarbonyl-N-substituted benzoylhydrazine 2a–e
(41.40 mmol) in methanol (100 mL) was added 5% Pd-C. Hydrogen gas
was then admitted to the solution. The reaction was monitored by TLC and
stopped after complete consumption of 2a–e. The solid was filtered off and
the filtrate was concentrated under vacuum to obtain a white powder.
3a. m.p. 127–1298C. (literature m.p.: 124–1258C)[16] 1H NMR (CDCl3,
200 MHz) d 1.48 (s, 9H, But), 3.90 (s, 2H, NH2), 7.28–7.56 (m, 5H, Ph).
1
3b. m.p. 128–1308C. H NMR (CDCl3, 200 MHz) d 1.48 (s, 9H, But),
2.34 (s, 6H, Me), 4.08 (s, 2H, NH2), 7.00–7.20 (m, 3H, Ph).
1
3c. m.p. 106–1078C. H NMR (CDCl3, 200 MHz) d 1.52 (s, 9H, But),
4.06 (s, 2H, NH2), 6.96–7.60 (m, 4H, Ph).
3d. m.p. 59–618C. 1H NMR (CDCl3, 200 MHz) d 1.52 (s, 9H, But), 4.00
(s, 2H, NH2), 7.20–7.60 (m, 4H, Ph).

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Wang and Huang
3e. m.p. 103–1058C. H NMR (CDCl3, 200 MHz) d 1.50 (s, 9H, But),
3.88 (s, 2H, NH2), 7.20–7.50 (m, 3H, Ph).
1
N-tert-Butyl-N-Substituted Benzoylhydrazines 3a, 3f–g
N-tert-Butyl-N0-phenyloxycarbonyl-N-substituted
benzoylhydrazine
(8.00 mmol) was dissolved in lukewarm ethanol (40 mL). While the reaction
mixture was stirred, a 15% aqueous solution of sodium hydroxide (50 mL) was
added. Following the addition, the mixture was stirred at 608C for 1 hr, then
cooled, and extracted three times with 100 mL of chloroform. The extraction
solvent was dried over anhydrous magnesium sulfate and filtered. The solvent
was removed by distillation to give a white solid. The solid was then
recrystallized from isopropanol and petroleum ether to obtain a colorless
crystalline solid.
1
3a. m.p. 127–1298C. H NMR (CDCl3, 200 MHz) d: 1.48 (s, 9H, But),
3.90 (s, 2H, NH2), 7.28–7.56 (m, 5H, Ph). IR (KBr): 3276.0 (NH2), 1620.5
(C55O), 1573.1, 1529.5, 1508.8 (Ph), 1375.6, 1350.0 (But), 719.6, 696.7 (Ph)
cm21
.
3f. m.p. 98–1008C. 1H NMR (CDCl3, 200 MHz) d: 1.45 (s, 9H, But), 2.36
(s, 3H, Me), 3.78 (br., 2H, NH2), 7.28 (m, 4H, Ph). Anal. Calcd. for
C12H18N2O (%): C, 69.87; H, 8.79; N, 13.58. Found: C, 69.85; H, 8.88; N,
13.56.
1
3g. m.p. 151–1528C. H NMR (CDCl3, 200 MHz) d: 1.45 (s, 9H, But),
3
3.80 (s, 3H, OMe), 4.00 (br., 2H, NH2), 6.85, 7.48 (dd, 4H, JHH ¼ 8.4 Hz,
Ph). Anal. Calcd. for C12H18N2O (%): C, 64.84; H, 8.16; N, 12.60. Found: C,
64.42; H, 8.42; N, 12.78.
General Procedure for the Preparation of N0-tert-Butyl-N0-
Substituted Benzoyl-N-(Substituted Phenyl)-
aminocarbonylhydrazines (6a–m)
To a stirred solution of the N-tert-butyl-N-substituted benzoylhydrazine
(3) (2.17 mmol) in 1,2-dichloroethane (10 mL) was added dropwise a solution
of a substituted phenylisocyanate (2.17 mmol) in 1,2-dichloroethane (5 mL) at
room temperature. After the addition, the resulting mixture was stirred at
reflux temperature. The reaction was monitored by TLC and stoped after
complete consumption of 3. The reaction mixture was diluted with petroleum
ether (60–908C) and filtered to afford a white solid. The crude solid was
recrystallized from dimethylformamide to obtain an analytical sample of 6a–
m. The preparative and spectral data of 6a–m are listed in Tables 3–5.

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Benzoyl-N-(Substituted Phenyl)aminocarbonylhydrazines
263
General Procedure for the Preparation of the Compounds (7)
N0-tert-butyl-N0-substituted benzoyl-N-(substituted phenyl)aminocar-
bonylhydrazine (6) (3.27 mmol) and oxalyl chloride (0.50 g) were dissolved
in 25 mL of 1,2-dichloroethane and boiled for 24 hr. The solvent was removed
under vacuum, and the residue was purified by column chromatography on
silica gel using a mixture of petroleum ether (60–908C) and ethyl acetate as
the eluent. Finally, the colourless crystalline (7) was obtained. The preparative
and spectral data of 7m are listed in Tables 3–5.
ACKNOWLEDGMENTS
We gratefully acknowledge support of this work by the National Natural
Science Foundation of China (20202005) and the Research Fund for the
Doctoral Program of Higher Education (20010055006) and the Foundation for
the author of National Excellent Doctoral Dissertation of P.R. China (200255).
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Received in Japan May 12, 2003

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